Intrinsic and Network Contributions to Reverberatory Activity: Reactive Clamp and Modeling Studies

Abstract

Cortical cells belong to small interconnected ensembles. These ensembles have the potential of being activated in a reverberatory fashion in vitro and in vivo, spontaneously or in response to stimulation. We combined computer simulations and in vitro intracellular recording from prefrontal cortical neurons to explore the elicitation, modulation, and termination of these reverberations. In computer simulations, we studied the reverberating activity of small networks of neurons connected with realistic stochastic synaptic transmission and concluded that about 40 excitatory cells and a few interneurons were sufficient to reproduce the membrane and firing characteristics observed in vivo. Using a variant of the dynamic-clamp technique in vitro, we then stimulated the assembly and triggered self-sustained activity mimicking the activity recorded during the delay period of a working memory task in the behaving monkey. The onset of sustained activity depended on the number of action potentials elicited by the cue-like stimulation. Too few spikes failed to provide enough NMDA current to drive sustained reverberations; too many spikes activated a slow intrinsic hyperpolarizing current that prevented spiking; an intermediate number of spikes produced sustained activity. The firing rate during the delay period could be effectively modulated by the standard deviation of the inhibitory background synaptic noise without significant changes in the background firing rate before cue-onset. These results suggest that the balance between fast feedback inhibition and slower AMPA and NMDA feedback excitation is critical in initiating persistent activity, that intrinsic currents may determine which cell contributes to the onset or offset of reverberations and that the maintenance of persistent activity may be regulated by the amount of correlated background inhibition.